The present invention relates to 6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ones which inhibit the extracellular release of inflammatory cytokines, said cytokines responsible for one or more human or higher mammalian disease states. The present invention further relates to compositions comprising said 6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ones and method for preventing, abating, or otherwise controlling enzymes which are understood to be the active components responsible for the herein described disease states.
Interleukin-1 (IL-1) and Tumor Necrosis Factor-xcex1 (TNF-xcex1) are among the important biological substances known collectively as xe2x80x9ccytokines.xe2x80x9d These molecules are understood to mediate the inflammatory response associated with the immunological recognition of infectious agents.
These pro-inflammatory cytokines are suggested as an important mediators in many disease states or syndromes, inter alia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease (IBS), septic shock, cardiopulmonary dysfunction, acute respiratory disease, cachexia, and therefore responsible for the progression and manifestation of human disease states.
There is therefore a long felt need for compounds and pharmaceutical compositions which comprise compounds, which can block, abate, control, mitigate, or prevent the release of cytokines from cells which produce them
The present invention meets the aforementioned needs in that it has been surprisingly found that certain bicyclic pyrazolones and derivatives thereof are effective for inhibiting release of inflammatory cytokines, inter alia, interleukin-1 (IL-1) and tumor necrosis factor (TNF) from cells and thereby preventing, abating, or otherwise controlling enzymes which are proposed to be the active components responsible for the herein described disease states.
The first aspect of the present invention relates to compounds, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, said compounds having the formula: 
wherein
R is:
a) xe2x80x94O[CH2]kR3; or
b) xe2x80x94N R4aR4b;
R3 is substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or alkylenearyl, substituted or unsubstituted heteroaryl or alkyleneheteroaryl; the index k is from 0 to 5;
R4a and R4b are each independently:
a) hydrogen; or
b) xe2x80x94[C(R5aR5b)]mR6;
each R5a and R5b are independently hydrogen, xe2x80x94OR7, xe2x80x94N(R7)2, xe2x80x94CO2R7, xe2x80x94CON(R7)2; C1-C4 linear, branched, or cyclic alkyl, and mixtures thereof; R6 is hydrogen, xe2x80x94OR7, xe2x80x94N(R7)2, xe2x80x94CO2R7, xe2x80x94CON(R7)2; substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R7 is hydrogen, a water-soluble cation, C1-C4 alkyl, or substituted or unsubstituted aryl; the index m is from 0 to 5;
R1 is:
a) substituted or unsubstituted aryl; or
b) substituted or unsubstituted heteroaryl;
each R2 unit is independently selected from the group consisting of:
a) hydrogen;
b) xe2x80x94(CH2)jO(CH2)nR8;
c) xe2x80x94(CH2)jNR9aR9b;
d) xe2x80x94(CH2)jCO2R10;
e) xe2x80x94(CH2)jOCO2R10 
f) xe2x80x94(CH2)jCON(R10)2;
g) xe2x80x94(CH2)jOCON(R10)2;
h) two R2 units can be taken together to form a carbonyl unit;
i) and mixtures thereof;
R8, R9a, R9b, and R10 are each independently hydrogen, C1-C4 alkyl, and mixtures thereof; R9a and R9b can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two R10 units can be take together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5, n is an index from 0 to 5;
Z is O, S, NR11, or NOR11; R11 is hydrogen or C1-C4 alkyl.
Another aspect of the present invention relates to pharmaceutical compositions which can deliver the compounds of the present invention to a human or higher mammal, said compositions comprising:
a) an effective amount of one or more of the compounds according to the present invention; and
b) one or more pharmaceutically acceptable excipients.
A further aspect of the present invention relates to methods for controlling one or more inflammatory cytokine mediated or inflammatory cytokine modulated mammalian diseases or conditions, said method comprising the step of administering to a human or higher mammal and effective amount of a composition comprising one or more of the compounds according to the present invention.
Another aspect of the present invention relates to forms of the compounds of the present invention, which under normal physiological conditions, will release the compounds as described herein.
These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (xc2x0 C.) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.
The present invention relates to compounds which are capable of mediating, controlling or otherwise inhibiting the extracellular release of certain cytokines, especially inflammatory cytokines, said cytokines playing a role in the stimulation, cause or manifestation of a wide variety of diseases, disease states, or syndromes.
For the purposes of the present invention the term xe2x80x9chydrocarbylxe2x80x9d is defined herein as any organic unit or moiety which is comprised of carbon atoms and hydrogen atoms. Included within the term hydrocarbyl are the heterocycles which are described herein below. Examples of various unsubstituted non-heterocyclic hydrocarbyl units include pentyl, 3-ethyloctanyl, 1,3-dimethylphenyl, cyclohexyl, cis-3-hexyl, 7,7-dimethylbicyclo[2.2.1]-heptan-1-yl, and naphth-2-yl.
Included within the definition of xe2x80x9chydrocarbylxe2x80x9d are the aromatic (aryl) and non-aromatic carbocyclic rings, non-limiting examples of which include cyclopropyl, cyclobutanyl, cyclopentanyl, cyclohexane, cyclohexenyl, cycloheptanyl, bicyclo-[0.1.1]-butanyl, bicyclo-[0.1.2]-pentanyl, bicyclo-[0.1.3]-hexanyl (thujanyl), bicyclo-[0.2.2]-hexanyl, bicyclo-[0.1.4]-heptanyl (caranyl), bicyclo-[2.2.1]-heptanyl (norboranyl), bicyclo-[0.2.4]-octanyl (caryophyllenyl), spiropentanyl, diclyclopentanespiranyl, decalinyl, phenyl, benzyl, naphthyl, indenyl, 2H-indenyl, azulenyl, phenanthryl, anthryl, fluorenyl, acenaphthylenyl, 1,2,3,4-tetrahydronaphthalenyl, and the like.
The term xe2x80x9cheterocyclexe2x80x9d includes both aromatic (heteroaryl) and non-aromatic heterocyclic rings non-limiting examples of which include: pyrrolyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrazolyl, 2H-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazoyl, 1,2,4-oxadiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-pyran-2-one-yl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, s-triazinyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 1,4-oxazinyl, morpholinyl, azepinyl, oxepinyl, 4H-1,2-diazepinyl, indenyl 2H-indenyl, benzofuranyl, isobenzofuranyl, indolyl, 3H-indolyl, 1H-indolyl, benzoxazolyl, 2H-1-benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl, 2H-1,4-benzoxazinyl, pyrrolidinyl, pyrrolinyl, quinoxalinyl, furanyl, thiophenyl, benzimidazolyl, and the like each of which can be substituted or unsubstituted.
An example of a unit defined by the term xe2x80x9calkylenearylxe2x80x9d is a benzyl unit having the formula: 
whereas an example of a unit defined by the term xe2x80x9calkyleneheteroarylxe2x80x9d is a 2-picolyl unit having the formula: 
The term xe2x80x9csubstitutedxe2x80x9d is used throughout the specification. The term xe2x80x9csubstitutedxe2x80x9d is defined herein as xe2x80x9cencompassing moieties or units which can replace a hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety. Also substituted can include replacement of hydrogen atoms on two adjacent carbons to form a new moiety or unit.xe2x80x9d For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. Three hydrogen replacement includes cyano, and the like. An epoxide unit is an example of a substituted unit which requires replacement of a hydrogen atom on adjacent carbons. The term substituted is used throughout the present specification to indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkyl chain, can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as xe2x80x9csubstitutedxe2x80x9d any number of the hydrogen atoms may be replaced. For example, 4-hydroxyphenyl is a xe2x80x9csubstituted aromatic carbocyclic ringxe2x80x9d, (N,N-dimethyl-5-amino)octanyl is a xe2x80x9csubstituted C8 alkyl unit, 3-guanidinopropyl is a xe2x80x9csubstituted C3 alkyl unit,xe2x80x9d and 2-carboxypyridinyl is a xe2x80x9csubstituted heteroaryl unit.xe2x80x9d The following are non-limiting examples of units which can serve as a replacement for hydrogen atoms when a hydrocarbyl unit is described as xe2x80x9csubstituted.xe2x80x9d
i) xe2x80x94[C(R12)2]p(CHxe2x95x90CH)qR12; wherein p is from 0 to 12; q is from 0 to 12;
ii) xe2x80x94C(Z)R12;
iii) xe2x80x94C(Z)2R12;
iv) xe2x80x94C(Z)CHxe2x95x90CH2;
v) xe2x80x94C(Z)N(R12)2;
vi) xe2x80x94C(Z)NR12N(R12)2;
vii) xe2x80x94CN;
viii) xe2x80x94CNO;
ix) xe2x80x94CF3, xe2x80x94CCl3, xe2x80x94CBr3;
Z) xe2x80x94N(R12)2;
xi) xe2x80x94NR12CN;
xii) xe2x80x94NR12C(Z)R12;
xiii) xe2x80x94NR12C(Z)N(R12)2;
xiv) xe2x80x94NHN(R12)2;
xv) xe2x80x94NHOR12;
xvi) xe2x80x94NCS;
xvii) xe2x80x94NO2;
xviii) xe2x80x94OR12;
xix) xe2x80x94OCN;
xx) xe2x80x94OCF3, xe2x80x94OCCl3, xe2x80x94OCBr3;
xxi) xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, and mixtures thereof;
xxii) xe2x80x94SCN;
xxiii) xe2x80x94SO3M;
xxiv) xe2x80x94OSO3M;
xxv) xe2x80x94SO2N(R12)2;
xxvi) xe2x80x94SO2R12;
xxvii) xe2x80x94P(O)H2;
xxviii) xe2x80x94PO2;
xxix) xe2x80x94P(O)(OH)2;
xxx) and mixtures thereof;
wherein R12 is hydrogen, substituted or unsubstituted C1-C20 linear, branched, or cyclic alkyl, C6-C20 aryl, C7-C20 alkylenearyl, and mixtures thereof; M is hydrogen, or a salt forming cation; Z is xe2x95x90O, xe2x95x90S, xe2x95x90NR11, and mixtures thereof. Suitable salt forming cations include, sodium, lithium, potassium, calcium, magnesium, ammonium, and the like.
The first aspect of the present invention relates to compounds having the formula: 
which are 2-R1-substituted-3-(2-R-substituted-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ones.
The second aspect of the present invention relates to compounds having the formula: 
which are 2-R1 substituted-3-(2-R-substituted-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-thiones.
The third aspect of the present invention relates to compounds having the formula: 
which are 2-R1 substituted-3-(2-R-substituted-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ylideneamines and derivatives thereof.
R is a substituent at the 2-position of the pyrimidin-4-yl portion of the general scaffold, said R unit is:
a) an ether having the formula xe2x80x94O[CH2]kR3; or
b) a primary or secondary amino unit having the formula xe2x80x94NR4aR4b;
wherein R3 is substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted cyclic hydrocarbyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or alkylenearyl, substituted or unsubstituted heteroaryl or alkyleneheteroaryl; the index k is from 0 to 5.
The following are the various aspects of R units according to the present invention wherein R is an ether having the formula xe2x80x94O[CH2]kR3. However, the formulator is not limited to the herein exemplified iterations and examples.
A) R units encompassing ethers having the formula xe2x80x94OR3 (the index k equal to 0) and R3 is substituted or unsubstituted aryl.
i) One iteration of this aspect of R comprises ethers having the formula xe2x80x94OR3 and R3 is substituted or unsubstituted aryl. This iteration includes the following non-limiting example of R: phenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 2,4-difluorophenoxy, 3-trifluoromethylphenoxy, 4-trifluoromethylphenoxy, 2,4-trifluoromethylphenoxy, and the like.
ii) Another iteration of this aspect of R comprises ethers having the formula xe2x80x94OR3 and R3 is substituted or unsubstituted aryl. This iteration includes the following non-limiting examples: 2-methylphenoxy, 3-methylphenoxy, 4-methylphenoxy, 2,4-dimethylphenoxy, 2-cyanophenoxy, 3-cyanophenoxy, 4-cyanophenoxy, 4-ethylphenoxy, and the like.
iii) A further iteration of this aspect of R comprises ethers having the formula xe2x80x94OR3 and R3 is substituted or unsubstituted aryl. This iteration includes the following non-limiting examples: (2-methyoxy)phenoxy, (3-methoxy)phenoxy, (4-methoxy)phenoxy, 3-[(N-acetyl)amino]phenoxy, 3-benzo[1,3]dioxol-5-yl, and the like.
B) R units encompassing ethers having the formula xe2x80x94OR3 (the index k equal to 0) and R3 is substituted or unsubstituted heteroaryl.
i) A first iteration of this aspect of R comprises ethers having the formula xe2x80x94OR3 and R3 is unsubstituted heteroaryl. This iteration includes the following non-limiting examples: pyrimidin-2-yl, pyrimidin-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and the like.
ii) A second iteration of this aspect of R comprises ethers having the formula xe2x80x94OR3 and R3 is substituted heteroaryl. This iteration includes the following non-limiting examples: 2-aminopyrimidin-4-yl, and the like.
C) R units encompassing ethers having the formula xe2x80x94OCH2R3 (the index k equal to 1) and R3 is substituted or unsubstituted aryl.
i) A first iteration of this aspect of R comprises ethers having the formula xe2x80x94OCH2R3 and R3 is substituted or unsubstituted heteroaryl. This iteration includes the following non-limiting examples: pyrimidin-2-yl, pyrimidin-4-yl, 2-aminopyrimidin-4-yl, 4-aminopyrimidin-6-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and the like.
ii) A second iteration of this aspect of R wherein R is an ether having the formula xe2x80x94OCH2R3 and R3 is substituted or unsubstituted alkyleneheteroaryl-aryl. This iteration includes the following non-limiting examples: pyridin-3-ylethyl, (2-methyl-2-pyridin-3-yl)ethyl, and the like.
D) R units encompassing ethers having the formula xe2x80x94OR3 (the index k equal to 1) and R3 is R3 is substituted or unsubstituted C1-C4 alkyl.
i) A first iteration of this aspect of R is an ether having the formula xe2x80x94OR3 and R3 is unsubstituted C1-C4 linear, branched, or cyclic alkyl. This iteration includes the following non-limiting examples: methyl, ethyl, isopropyl, (S)-1-methypropyl, and the like.
ii) A second iteration of this aspect of R is an ether having the formula xe2x80x94OR3 and R3 is a substituted C1-C4 linear, branched, or cyclic alkyl. This iteration includes the following non-limiting examples: 2-methoxyethyl, (S)-1-methy-3-methyoxypropyl, and the like.
The following are the various aspects of R units according to the present invention wherein R is an amine having the formula xe2x80x94NR4aR4b, R4a and R4b are each independently:
a) hydrogen; or
b) xe2x80x94[C(R5aR5b)]mR6;
each R5a and R5b are independently hydrogen, or C1-C4 linear, branched, xe2x80x94OR7, xe2x80x94N(R7)2, xe2x80x94CO2R7, xe2x80x94CON(R7)2; cyclic alkyl, and mixtures thereof; R6 is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; xe2x80x94OR7, xe2x80x94N(R7)2, xe2x80x94CO2R7, xe2x80x94CON(R7)2, R7 is hydrogen, a water-soluble cation, C1-C4 alkyl, or substituted or unsubstituted aryl; the index m is from 0 to 5. However, the formulator is not limited to the herein exemplified iterations and examples.
A) R units encompassing chiral amino groups wherein R4a is hydrogen, R5a is hydrogen and R5b is methyl, said units having the formula: 
xe2x80x83and the indicated stereochemistry.
i) A first iteration of this aspect of R is an amine comprising an R6 which is substituted or unsubstituted phenyl. This iteration includes the following non-limiting examples: (S)-1-methyl-1-phenylmethylamino, (S)-1-methyl-1-(4-fluorophenyl)methylamino, (S)-1-methyl-1-(4-methylphenyl)methyl-amino, (S)-1-methyl-1-(4-methoxyphenyl)methylamino, (S)-1-methyl-1-(2-aminophenyl)methylamino, (S)-1-methyl-1-(4-aminophenyl)methylamino, and the like.
ii) A second iteration of this aspect of R is an amine comprising an R6 which is substituted or unsubstituted heteroaryl. This iteration includes the following non-limiting examples: (S)-1-methyl-1-(pyridin-2-yl)methylamino, (S)-1-methyl-1-(pyridin-3-yl)methylamino, (S)-1-methyl-1-(pyridin-4-yl)methylamino, (S)-1-methyl-1-(furan-2-yl)methylamino, (S)-1-methyl-1-(3-benzo[1,3]dioxol-5-yl)methylamino, and the like.
iii) A third iteration of this aspect of R is an amine comprising an R6 which is C1-C4 substituted or unsubstituted alkyl. This iteration includes the following non-limiting examples: (S)-1-methylpropylamino, (S)-1-methyl-2-(methoxy)ethylamino.
B) R units encompassing chiral amino groups wherein R4a is hydrogen, R5a and R5b are each C1-C4 alkyl, said units having the formula: 
xe2x80x83and the indicated stereochemistry when R5a, R5b and R6 are not the same.
i) A first iteration of this aspect of R is an amine which does not have a chiral center, non-limiting examples of which includes 1,1-dimethylethylamine, 1,1-dimethylbenzylamine and the like.
ii) A second iteration of this aspect of R is an amine comprising an R6 which is substituted or unsubstituted C1-C4 alkyl. This iteration includes the following non-limiting examples: (S)-1-methyl-2-hydroxy-2-methylpropylamine, (S)-1-methyl-2-hydroxy-2-methylbutylamine, and the like.
C) R units encompassing alkylenearyl amines wherein R4a is hydrogen, both R5a and R5b of R4b are hydrogen, R6 is substituted or unsubstituted aryl, said unit having the formula: 
xe2x80x83wherein R11 is hydrogen or a xe2x80x9csubstituted unitxe2x80x9d as defined herein above.
i) A first iteration of this aspect comprises the following non-limiting examples of R units: benzylamino, (2-aminophenyl)methylamino; (4-fluorophenyl)methylamino, (4-methoxyphenyl)methylamino; (4-propanesulfonylphenyl)methylamino; and the like.
ii) A second iteration of this aspect comprises the following non-limiting examples of R units: (2-methylphenyl)methylamino; (3-methylphenyl)-methylamino; (4-methylphenyl)methylamino; and the like.
D) R units encompassing amines wherein R4a is hydrogen, R4b comprises R5a equal to hydrogen and R5b equal to xe2x80x94CO2R7 or xe2x80x94CON(R7)2; said unit having the formula: 
i) A first iteration of this aspect of R is an amine comprising an R6 which is substituted or unsubstituted phenyl. This iteration includes the following non-limiting examples: 
xe2x80x83wherein R11 is hydrogen or a xe2x80x9csubstitutexe2x80x9d as defined herein above.
ii) A second iteration of this aspect of R6 is an amine comprising an R6 which is substituted or unsubstituted alkyl. This iteration includes the following non-limiting examples: 
R1 units are selected from:
a) substituted or unsubstituted aryl; or
b) substituted or unsubstituted heteroaryl.
The first aspect of R1 units encompasses halogen substituted phenyl units, non-limiting examples of which include 4-fluorophenyl, 2,4-difluorophenyl, 4-chlorophenyl, and the like.
Each R2 unit is independently selected from the group consisting of:
a) hydrogen;
b) xe2x80x94(CH2)jO(CH2)nR8;
c) xe2x80x94(CH2)jNR9aR9b;
d) xe2x80x94(CH2)jCO2R10; 
e) xe2x80x94(CH2)jOCO2R10 
f) xe2x80x94(CH2)jCON(R10)2;
g) xe2x80x94(CH2)jOCON(R10)2;
h) two R2 units can be taken together to form a carbonyl unit;
i) and mixtures thereof;
R8, R9a, R9b, and R10 are each independently hydrogen, C1-C4 alkyl, and mixtures thereof; R9a and R9b can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two R10 units can be take together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5, n is an index from 0 to 5.
The first aspect of the present invention relating to R2 encompasses scaffolds having the formula: 
wherein each R2 unit is hydrogen.
A second aspect relates to scaffolds having the formula: 
wherein R8 is hydrogen or C1-C4 alkyl.
A third aspect relates to scaffolds having the formula: 
wherein R9a and R9b are each independently hydrogen, methyl, or R9a and R9b can be taken together to form a piperidine or morpholine ring.
A fourth aspect relates to scaffolds having the formula: 
wherein one R2 is xe2x80x94CO210 and the other R2 units are hydrogen; one R10 is hydrogen or methyl.
Z is O, S, NR11, or NOR11; R11 is hydrogen or C1-C4 alkyl. The first aspect of the present invention as it relates to Z units, comprises oxygen atoms which provide 2-R1 substituted-3-(2-R-substituted-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ones, the second aspect relates to Z units comprising sulfur atoms which provide 2-R1 substituted-3-(2-R-substituted-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-thiones, and the third aspect of the present invention as it relates to Z units, comprises NR11 units thereby providing 2-R1 substituted-3-(2-R-substituted-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ylideneamines and derivatives thereof.
The first category of inflammatory cytokine release inhibiting compounds according to the present invention have the general scaffold having the formula: 
wherein R units are ethers having the formula xe2x80x94OR3, wherein R1 and R3 are described herein below in Table I
The analogs 1-48 and others like them which comprise this category can be suitably prepared by the procedure outlined herein below. In the following example, R1 is 4-fluorophenyl, however, the formulator may suitably substitute any starting material compatible with this procedure, inter alia, methyl phenylacetate, methyl 4-chlorophenyl-acetate, and methyl 3-(trifluoromethyl)phenylacetate. 